Controlled drug release from poly(ortho esters) — A surface eroding polymer

Abstract

Poly(ortho esters) are a polymer system containing backbone linkages that are stable in base, hydrolyze at very slow rates at the physiological pH of 7.4, and become progressively more labile as the pH is lowered. A major rationale for developing this system was a need for a polymer capable of a wide variety of erosion rates and where erosion could be confined to the surface of a solid device. Surface erosion and variations in delivery rates of therapeutic agents physically incorporated into the polymer can be achieved by either stabilizing the interior of the polymer with a base so that erosion can take place only in the surface layers where the basic excipient is neutralized by the external medium or by using acidic excipients incorporated into the typically highly hydrophobic matrix. In this latter case, surface erosion takes place only in the surface layer where the excipient is exposed to water. Poly(ortho esters) can be prepared by means of a general synthesis that involves the addition of diols to ketene acetals. The reaction is catalyzed by traces of acid, is exothermic, and proceeds to completion virtually instantaneously. Because no small-molecule by-products are evolved, dense, crosslinked materials can be produced by using varying proportions of monomers having a functionality greater than two. For long-term release studies (6–12 months) we have investigated two approaches. In one approach we have used a linear polymer prepared from 3,9-bis(ethylidene 2,4,8,10-tetraoxaspiro[5,5] undecane) and various mole ratios of 1,6-hexanediol and trans-cyclohexane-dimethanol. Varying this ratios allowed variations in the glass transition temperature from a low of 20°C to a high of 120°C. Erosion rate of the polymer was controlled by incorporation of the slightly acidic, low water solubility salt, calcium lactate. However, using this approach rate of polymer erosion was higher than the rate at which the highly water insoluble levonorgestrel can solubilize so that release rate of leuonorgestrel from the devices was controlled by its rate of dissolution. In the second approach we have used a crosslinked polymer where the interior of the device has been stabilized with the basic, low water solubility salt Mg(OH) 2. Using this approach, polymer erosion is confined to the surface of the rod-shaped devices. Rate of polymer erosion can be manipulated by the copolymerization of 9,10-dihydroxystearic acid into the crosslinked matrix. Short-term erosion studies and concomitant drug release have been investigated by Himmel-stein. Sparer and Shih at Interx using acid anhydrides to catalyze polymer erosion. Using this approach devices having lifetimes between hours and about one month could be prepared.